Hormonal regulation of hepatic gluconeogenesis and glycolysis

Gluconeogenesis is the energy-demanding process whereby lactate, pyruvate, glycerol, and certain amino acids are converted to glucose and glycogen. The liver is the major site of gluconeogenesis, although the kidney becomes important during prolonged starvation. The most important function of gluconeogenesis is the maintenance of blood glucose levels during times when food intake is restricted and/or glycogen stores are depleted. For example, the rate of gluconeogenesis is enhanced during starvation and in the diabetic state. It is also the means whereby the lactate that is produced by glycolysis in erythrocytes and in exercising muscle is reconverted to glucose. Similarly, it conserves the glycerol that is released during lipolysis in adipose tissue and the alanine produced by amino acid metabolism and glycolysis in muscle. Gluconeogenesis also contributes significantly to the utilization of amino acids, which are either absorbed from the alimentary tract or released during protein breakdown in muscle and other tissues. Glycolysis is the reverse of gluconeogenesis. It is the metabolic sequence that converts glucose to pyruvate and lactate and provides energy. The liver, however, does not glycolyze at high rates, except during anoxia or when high concentrations of glucose are present. It has been proposed that the major function of hepatic glycolysis is to provide substrates for fatty acid synthesis, but it may also provide them for glycogen synthesis. These two opposing processes must be regulated in a concerted fashion in order to permit the net synthesis of either glucose or lactate and pyruvate to occur. An important caveat when considering data on regulation of hepatic gluconeogenesis and glycolysis is that the majority of our information comes from studies on rat liver and it may not be totally transferable to human or other livers. Regulation of gluconeogenesis/glycolysis can be divided for convenience into three categories. The first involves regulation of the supply of substrate. All gluconeogenic substrates as well as glucose reach the liver in subsaturating concentrations. Thus regulation of substrate release into the blood from extrahepatic tissues or provision of substrate from the diet will directly affect hepatic glucose formation and ultization. The second category involves the very important but relatively slow (hours-to-days) adaptive changes in enzyme activity due to regulation of gene expression, protein synthesis, and/or degradation. The third category is concerned with the minute-to-minute regulation of pathway flux due to changes in the phosphorylation state and/or allosteric effectors of key enzymes through the action of hormones such as insulin, glucagon, and catecholamines. This review focuses on the second and third categories. While the emphasis is on short- and long-term regulation of enzyme activities, it is clear that regulation in vivo involves integration of all three categories. This review concentrates on advances in our understanding of the properties and regulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, and then attempts to provide an integrated view of the regulation of pathway flux by both short- and long-term hormonal modulation.